Mutant EZH2 Induces a Pre-malignant Lymphoma Niche by Reprogramming the Immune Response

Wendy Béguelin, Matt Teater, Cem Meydan, Kenneth B. Hoehn, Jude M. Phillip, Alexey A. Soshnev, Leandro Venturutti, Martín A. Rivas, María T. Calvo-Fernández, Johana Gutierrez, Jeannie M. Camarillo, Katsuyoshi Takata, Karin Tarte, Neil L. Kelleher, Christian Steidl, Christopher E. Mason, Olivier Elemento, C. David Allis, Steven H. Kleinstein, Ari M. Melnick

Research output: Contribution to journalArticlepeer-review

Abstract

Follicular lymphomas (FLs) are slow-growing, indolent tumors containing extensive follicular dendritic cell (FDC) networks and recurrent EZH2 gain-of-function mutations. Paradoxically, FLs originate from highly proliferative germinal center (GC) B cells with proliferation strictly dependent on interactions with T follicular helper cells. Herein, we show that EZH2 mutations initiate FL by attenuating GC B cell requirement for T cell help and driving slow expansion of GC centrocytes that become enmeshed with and dependent on FDCs. By impairing T cell help, mutant EZH2 prevents induction of proliferative MYC programs. Thus, EZH2 mutation fosters malignant transformation by epigenetically reprograming B cells to form an aberrant immunological niche that reflects characteristic features of human FLs, explaining how indolent tumors arise from GC B cells.

Original languageEnglish (US)
Pages (from-to)655-673.e11
JournalCancer cell
Volume37
Issue number5
DOIs
StatePublished - May 11 2020
Externally publishedYes

Keywords

  • EZH2
  • epigenetic dysregulation
  • follicular lymphoma
  • germinal center
  • immune microenvironment

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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